Citation and License

Arthritis Research & Therapy 2011, 13:R114
doi:10.1186/ar3399

Published: 12 July 2011

Abstract

Introduction

Mouse models of rheumatoid arthritis (RA) have proven critical for identifying genetic
and cellular mechanisms of the disease. Upon discovering mice in our breeding colony
that had spontaneously developed inflamed joints reminiscent of RA, we established
the novel IIJ (inherited inflamed joints) strain. The purpose of this study was to
characterize the histopathological, clinical, genetic and immunological properties
of the disease.

Methods

To begin the IIJ strain, an arthritic male mouse was crossed with SJL/J females. Inheritance
of the phenotype was then tracked by intercrossing, backcrossing and outcrossing to
other inbred strains. The histopathology of the joints and extraarticular organ systems
was examined. Serum cytokines and immunoglobulins (Igs) were measured by ELISA and
cytometric bead array. Transfer experiments tested whether disease could be mediated
by serum alone. Finally, the cellular joint infiltrate and the composition of secondary
lymphoid organs were examined by immunohistochemistry and flow cytometry.

Results

After nine generations of intercrossing, the total incidence of arthritis was 33%
(304 of 932 mice), with females being affected more than males (38% vs. 28%; P < 0.001). Swelling, most notably in the large distal joints, typically became evident
at an early age (mean age of 52 days). In addition to the joint pathology, which included
bone and cartilage erosion, synovial hyperproliferation and a robust cellular infiltration
of mostly Gr-1+ neutrophils, there was also evidence of systemic inflammation. IL-6 was elevated in
the sera of recently arthritic mice, and extraarticular inflammation was observed
histologically in multiple organs. Total serum Ig and IgG1 levels were significantly
elevated in arthritic mice, and autoantibodies such as rheumatoid factor and Ig reactive
to joint components (collagen type II and joint homogenate) were also detected. Nevertheless,
serum failed to transfer disease. A high percentage of double-negative (CD4-CD8-) CD3+ TCRα/β+ T cells in the lymphoid organs of arthritic IIJ mice suggested significant disruption
in the T-cell compartment.

Conclusions

Overall, these data identify the IIJ strain as a new murine model of inflammatory,
possibly autoimmune, arthritis. The IIJ strain is similar, both histologically and
serologically, to RA and other murine models of autoimmune arthritis. It may prove
particularly useful for understanding the female bias in autoimmune diseases.